The Caliciviridae is a family of positive-strand RNA viruses and consists of five genera designated: (1) Norovirus (with species Norwalk virus); (2) Sapovirus (with species Sapporo virus); (3) Vesivirus (with species, feline calicivirus and vesicular exanthema of swine virus); (4) Lagovirus (with species rabbit hemorrhagic disease virus and European brown hare syndrome virus) and (5) Nebovirus (with species Newbury-2 virus). The diseases caused by caliciviruses vary, according to the virus and its host species. Members of the Caliciviridae causing diarrheal disease in humans belong to the genera Norovirus and Sapovirus. The Caliciviruses Section (CS) in LID conducts research related to caliciviruses, with an emphasis on the noroviruses because of their predominant role in human diarrheal disease. Noroviruses are genetically-diverse and most human norovirus pathogens belong to either Genogroup I (GI) or Genogroup II (GII), with GII.4 as the predominant genotype. An important area of investigation in our laboratory is the role of genetic diversity in the natural history of norovirus infection, as this information is directly relevant to vaccine design. This year we completed a comprehensive analysis of norovirus genomic diversity and proposed that the evolutionary pattern for each GI or GII genotype can be classified into one of two patterns: static or evolving. The GII.4 noroviruses are the major strains with an evolving pattern of evolution, and we propose that the ability to acquire adaptive mutations rapidly is responsible for their predominance in the human population. We reviewed natural history studies and proposed patterns of antigenic relationships that we provisionally termed as immunotypes. Future studies with cross-neutralization assays will be required to confirm these relationships, and they are planned. Why is this important? It may be possible to formulate norovirus vaccines with fewer components if certain genotypes are found to be antigenically-related and cross-protective. High throughput technologies allowed new discoveries this year. siRNA screening and transcriptome analysis of murine norovirus (MNV), a replication model for the noroviruses because it grows efficiently in cell culture, showed the major cellular pathways that are up- and down- regulated during norovirus replication. Notably, the innate immune response is early and robust and interferon might be a potential treatment strategy for the noroviruses. Our laboratory gained expertise in stem-cell derived intestinal enteroids and the replication of human noroviruses in these cells is under investigation, along with plans to conduct high-throughput screening of repurposed drugs. A high-through screening of a human membrane proteins library led to the identification of JAM-1 as a receptor for an animal-origin calicivirus (Hom-1) that replicates in human cells. We continued an epidemiological investigation of noroviruses in immunocompromised patients enrolled in research protocols at the NIH Clinical Research Center and found that chronic norovirus infections were present in 12% or more of these patients. Our genomics work established that these infections were community-acquired and not hospital-acquired (nosocomial). We are expanding our studies of these patients to understand the pathogenesis of norovirus and how the virus adapts to become chronic. We aim to identify an effective therapeutic option for these patients and design a clinical trial to evaluate it.